Protective effects of histone deacetylase 6 specific inhibitor tubastatin A on subarachnoid hemorrhage in rats and the underlying mechanisms / 中南大学学报(医学版)

OBJECTIVES@#Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease. Early brain injury (EBI) and cerebral vasospasm are the main reasons for poor prognosis of SAH patients. The specific inhibitor of histone deacetylase 6 (HDAC6), tubastatin A (TubA), has been proved to have a definite neuroprotective effect on a variety of animal models of acute and chronic central nervous system diseases. However, the neuroprotective effect of TubA on SAH remains unclear. This study aims to investigate the expression and localization of HDAC6 in the early stage of SAH, and to evaluate the protective effects of TubA on EBI and cerebral vasospasm after SAH and the underlying mechanisms.@*METHODS@#Adult male SD rats were treated with modified internal carotid artery puncture to establish SAH model. In the first part of the experiment, rats were randomly divided into 6 groups: a sham group, a SAH-3 h group, a SAH-6 h group, a SAH-12 h group, a SAH-24 h group, and a SAH-48 h group. At 3, 6, 12, and 24 h after SAH modeling, the injured cerebral cortex of rats in each group was taken for Western blotting to detect the expression of HDAC6. In addition, the distribution of HDAC6 in the cerebral cortex of the injured side was measured by immunofluorescence double staining in SAH-24 h group rats. In the second part, rats were randomly divided into 4 groups: a sham group, a SAH group, a SAH+TubAL group (giving 25 mg/kg TubA), and a SAH+TubAH group (giving 40 mg/kg TubA). At 24 h after modeling, the injured cerebral cortex tissue was taken for Western blotting to detect the expression levels of HDAC6, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining to detect apoptosis, and hematoxylin and eosin (HE) staining to detect the diameter of middle cerebral artery.@*RESULTS@#The protein expression of HDAC6 began to increase at 6 h after SAH (P<0.05), peaked at 24 h (P<0.001), and decreased at 48 h, but there was still a difference compared with the sham group (P<0.05). HDAC6 is mainly expressed in the cytoplasm of the neurons. Compared with the sham group, the neurological score was decreased significantly and brain water content was increased significantly in the SAH group (both P<0.01). Compared with the SAH group, the neurological score was increased significantly and brain water content was decreased significantly in the SAH+TubAH group (both P<0.05), while the improvement of the above indexes was not significant in the SAH+TubAL group (both P>0.05). Compared with the sham group, the expression of eNOS was significantly decreased (P<0.01) and the expressions of iNOS and HDAC6 were significantly increased (P<0.05 and P<0.01, respectively) in the SAH group. Compared with the SAH group, the expression of eNOS was significantly increased, and iNOS and HDAC6 were significantly decreased in the SAH+TubA group (all P<0.05). Compared with the SAH group, the number of TUNEL positive cells was significantly decreased and the diameter of middle cerebral artery was significantly increased in the SAH+TubA group (both P<0.05) .@*CONCLUSIONS@#HDAC6 is mainly expressed in neurons and is up-regulated in the cerebral cortex at the early stage of SAH. TubA has protective effects on EBI and cerebral vasospasm in SAH rats by reducing brain edema and cell apoptosis in the early stage of SAH. In addition, its effect of reducing cerebral vasospasm may be related to regulating the expression of eNOS and iNOS.

Neuroprotective potential of cannabidiol: Molecular mechanisms and clinical implications / 中西医结合学报

Cannabidiol (CBD), a nonpsychotropic phytocannabinoid that was once largely disregarded, is currently the subject of significant medicinal study. CBD is found in Cannabis sativa, and has a myriad of neuropharmacological impacts on the central nervous system, including the capacity to reduce neuroinflammation, protein misfolding and oxidative stress. On the other hand, it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors. Because of this, CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives. Nonetheless, CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases. Currently, many clinical trials are being conducted to investigate this possibility. This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer's disease, Parkinson's disease and epilepsy. Overall, this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations, opening a new therapeutic window for neuroprotection. Please cite this article as: Tambe SM, Mali S, Amin PD, Oliveira M. Neuroprotective potential of Cannabidiol: Molecular mechanisms and clinical implications. J Integr Med. 2023; 21(3): 236-244.

Xixin Decoction improves learning and memory ability of SAMP8 by enhancing neuroprotective effect and inhibiting neuroinflammation / 中国中药杂志

This study aimed to explore the possible effect of Xixin Decoction(XXD) on the learning and memory ability of Alzheimer's disease(AD) model senescence-accelerated mouse-prone 8(SAMP8) and the related mechanism in enhancing neuroprotective effect and reducing neuroinflammation. Forty SAMP8 were randomly divided into a model group(10 mL·kg~(-1)·d~(-1)), a probiotics group(0.39 g·kg~(-1)·d~(-1)), a high-dose group of XXD granules(H-XXD, 5.07 g·kg~(-1)·d~(-1)), a medium-dose group of XXD granules(M-XXD, 2.535 g·kg~(-1)·d~(-1)), and a low-dose group of XXD granules(L-XXD, 1.267 5 g·kg~(-1)·d~(-1)). Eight senescence-accelerated mouse-resistant 1(SAMR1) of the same age and strain were assigned to the control group(10 mL·kg~(-1)·d~(-1)). After ten weeks of intragastric administration, the Morris water maze was used to test the changes in spatial learning and memory ability of mice after treatment. Meanwhile, immunofluorescence staining was used to detect the positive expression of receptor for advanced glycation end products(AGER), Toll-like receptor 1(TLR1), and Toll-like receptor 2(TLR2) in the hippocampal CA1 region of mice. Western blot was employed to test the protein expression levels of silencing information regulator 2 related enzyme 1(SIRT1), AGER, TLR1, and TLR2 in the hippocampus of mice. Enzyme linked immunosorbent assay(ELISA) was applied to assess the levels of Aβ_(1-42) in the hippocampus of mice and the levels of nuclear factor κB p65(NF-κB p65), NOD-like receptor protein 3(NLRP3), tumor necrosis factor-α(TNF-α), and interleukin-1β(IL-1β) in the serum and hippocampus of mice. Compared with the model group, XXD significantly improved the spatial learning and memory ability of SAMP8, increased the expression of neuroprotective factors in the hippocampus, decreased the levels of neuroinflammatory factors, and inhibited the expression of Aβ_(1-42). In particular, H-XXD significantly increased the expression of SIRT1 in the hippocampus of mice, reduced the expression levels of NF-κB p65, NLRP3, TNF-α, and IL-1β in the serum and hippocampus of mice, and decreased the expression of AGER, TLR1, and TLR2 in the hippocampus of mice(P<0.05 or P<0.01). XXD may improve the spatial learning and memory ability of AD model SAMP8 by enhancing the neuroprotective effect and inhibiting neuroinflammation.

Total Saponins of Panax notoginseng Activate Akt/mTOR Pathway and Exhibit Neuroprotection in vitro and in vivo against Ischemic Damage / 中国结合医学杂志

OBJECTIVE@#To reveal the neuroprotective effect and the underlying mechanisms of a mixture of the main components of Panax notoginseng saponins (TSPN) on cerebral ischemia-reperfusion injury and oxygen-glucose deprivation/reoxygenation (OGD/R) of cultured cortical neurons.@*METHODS@#The neuroprotective effect of TSPN was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and live/dead cell assays. The morphology of dendrites was detected by immunofluorescence. Middle cerebral artery occlusion (MCAO) was developed in rats as a model of cerebral ischemia-reperfusion. The neuroprotective effect of TSPN was evaluated by neurological scoring, tail suspension test, 2,3,5-triphenyltetrazolium chloride (TTC) and Nissl stainings. Western blot analysis, immunohistochemistry and immunofluorescence were used to measure the changes in the Akt/mammalian target of rapamycin (mTOR) signaling pathway.@*RESULTS@#MTT showed that TSPN (50, 25 and 12.5 µ g/mL) protected cortical neurons after OGD/R treatment (P<0.01 or P<0.05). Flow cytometry and live/dead cell assays indicated that 25 µ g/mL TSPN decreased neuronal apoptosis (P<0.05), and immunofluorescence showed that 25 µ g/mL TSPN restored the dendritic morphology of damaged neurons (P<0.05). Moreover, 12.5 µ g/mL TSPN downregulated the expression of Beclin-1, Cleaved-caspase 3 and LC3B-II/LC3B-I, and upregulated the levels of phosphorylated (p)-Akt and p-mTOR (P<0.01 or P<0.05). In the MCAO model, 50 µ g/mL TSPN improved defective neurological behavior and reduced infarct volume (P<0.05). Moreover, the expression of Beclin-1 and LC3B in cerebral ischemic penumbra was downregulated after 50 µ g/mL TSPN treatment, whereas the p-mTOR level was upregulated (P<0.05 or P<0.01).@*CONCLUSION@#TSPN promoted neuronal survival and protected dendrite integrity after OGD/R and had a potential therapeutic effect by alleviating neurological deficits and reversing neuronal loss. TSPN promoted p-mTOR and inhibited Beclin-1 to alleviate ischemic damage, which may be the mechanism that underlies the neuroprotective activity of TSPN.

Echinacoside Alleviates Cognitive Impairment in Cerebral Ischemia Rats through α 7nAChR-Induced Autophagy / 中国结合医学杂志

OBJECTIVES@#To evaluate the effect of echinacoside (ECH) on cognitive dysfunction in post cerebral stroke model rats.@*METHODS@#The post stroke cognitive impairment rat model was created by occlusion of the transient middle cerebral artery (MCAO). The rats were randomly divided into 3 groups by a random number table: the sham group (sham operation), the MCAO group (received operation for focal cerebral ischemia), and the ECH group (received operation for focal cerebral ischemia and ECH 50 mg/kg per day), with 6 rats in each group. The infarct volume and spatial learning were evaluated by triphenyl tetrazolium chloride staining and Morris water maze. The expression of α7nAChR in the hippocampus was detected by immunohistochemistry. The contents of acetylcholine (ACh), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), activities of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and catalase (CAT) were evaluated by enzyme linked immunosorbent assay. The neural apoptosis and autophagy were determined by TUNEL staining and LC3 staining, respectively.@*RESULTS@#ECH significantly lessened the brain infarct volume and ameliorated neurological deficit in infarct volume and water content (both P<0.01). Compared with MCAO rats, administration of ECH revealed shorter escape latency and long retention time at 7, 14 and 28 days (all P<0.01), increased the α7nAChR protein expression, ACh content, and ChAT activity, and decreased AChE activity in MCAO rats (all P<0.01). ECH significantly decreased MDA content and increased the GSH content, SOD, and CAT activities compared with MCAO rats (all P<0.05). ECH suppressed neuronal apoptosis by reducing TUNEL-positive cells and also enhanced autophagy in MCAO rats (all P<0.01).@*CONCLUSION@#ECH treatment helped improve cognitive impairment by attenuating neurological damage and enhancing autophagy in MCAO rats.

Research Progress of Pharmacological Intervention of Sevoflurane-induced Nerve Injury in the Developing Brain / 中国医学科学院学报

Sevoflurane is one of the most commonly used inhaled anesthetics in obstetric and pediatric general anesthesia.According to related literature,this article reviews major possible mechanisms including myelin formation damage,nerve inflammation,cell apoptosis,oxidative stress,inhibition of histone acetylation,synapsis and receptor changes of sevoflurane-induced neurotoxicity in animal experiments.Furthermore,we summarize the neuroprotection effects and functioning mechanisms of anti-anemia medicine,plant-based drugs,alpha 2 adrenoceptor agonists and others,aiming to provide a basis for the brain protection of fetuses and infants during the perioperative period.

Biological bases for a possible effect of cannabidiol in Parkinson's disease

Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.

Advances in research on pharmacological and neuroprotective effects of traditional Chinese medicine after cerebral ischemia / 中国中药杂志

Cerebral ischemia is also known as ischemic stroke. In recent years, research on neuroprotection after ischemia has became a hot spot as stroke can result in symptoms of nerve damages such as hemiplegia, learning and memory disorders. The key factors that cause the death of cells include excitotoxicity, oxidative damage, nitrosative stress and inflammation. However, there is no effective preparation for the treatment of post-ischemic nerve defects at present, so it is urgent to find and develop effective drugs for the treatment of nerve damages after ischemia. Traditional Chinese medicine has advantages and potentials in the treatment of neurological diseases. Many scholars have carried out related researches on the active ingredients of traditional Chinese medicine and achieved some good results. In this context, the researches on the neuroprotective effects of traditional Chinese medicines such as tetramethylpyrazine, butylphthalide and total saponins of Panax notoginseng were reviewed. The author found that the neuroprotective researches of traditional Chinese medicine mostly focused on anti-apoptosis, anti-inflammatory and anti-oxidative stress, but those effects were not sounique to the nervous system. Furthermore, most ingredients of traditional Chinese medicine showed a poor water-soluble property. In view of the research status and existing problems of traditional Chinese medicine in nerve injury, the suggestions for the research and development of the potent neuroprotective agents were proposed in this study from the perspective of pharmacological mechanism research and preparation theory.

Neuroprotective natural products: promising candidates against neurodegenerative diseases / Productos naturales con propiedades neuroprotectivas: posibles candidatos para el tratamiento de enfermedades neurodegenerativas

Neurodegeneration is a progressive loss of neurons both structurally and functionally causing neuronal cell death ultimately leading to development of various neurodegenerative diseases. Due to poor pharmacokinetic profile of neurotrophins, there still remains a challenge in their neurotrophic therapy where plants, bacteria and fungi, as natural products, could act as promising candidates against various neurological disorders by modulating the neurotrophic activity. Therefore, these natural products that mimic neurotrophins, could develop novel therapeutic approaches to herbal drug that can ameliorate neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other associated neurological disorders. Taking into account the failure of strategies involving single neurotrophins for the treatment of neurodegenerative diseases, we propose a combination of small molecules of natural products that may work synergistically to restore neuronal functions, minimize side effects and target multiple pathways for a more effective treatment.

La neurodegeneración es una pérdida progresiva de neuronas, tanto estructural como funcional, que causa la muerte neuronal, lo que conduce al desarrollo de diversas enfermedades neurodegenerativas. Debido al pobre perfil farmacocinético de las neurotrofinas, existe un desafío en su terapia neurotrófica donde plantas, bacterias y hongos, como productos naturales, podrían actuar como candidatos contra diversos trastornos neurológicos al modular la actividad neurotrófica. Estos productos naturales que asemejan a las neurotrofinas podrían desarrollar enfoques terapéuticos novedosos como medicamentos a base de hierbas que pueden mejorar enfermedades neurodegenerativas como: Parkinson, Alzheimer y otros trastornos neurológicos asociados. Teniendo en cuenta el fracaso de las estrategias terapéuticas de neurotrofinas para las enfermedades neurodegenerativas, proponemos una combinación de pequeñas moléculas de productos naturales que pueden funcionar sinérgicamente para restaurar las funciones neuronales, minimizar los efectos secundarios y apuntar a múltiples vías para un tratamiento más efectivo.

Effect of carbamylated erythropoietin on neuronal apoptosis in fetal rats during intrauterine hypoxic-ischemic encephalopathy

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a common disease that occurs during the perinatal period. The primary cause of neonatal HIE is related to fetal intrauterine anoxia. Carbamylated erythropoietin (CEPO), a derivative of erythropoietin (EPO), does not exert any erythropoietic effect; however, the neuroprotective effects resemble those of EPO. Previous studies have shown the potential benefits of CEPO on the central nervous system. The present study aimed to investigate the role of CEPO in neuronal apoptosis during intrauterine HIE and the underlying mechanisms. RESULTS: To validate our hypothesis, we established an intrauterine HIE model by occluding the bilateral uteroovarian arteries of pregnant Sprague-Dawley rats. Compared to the I/R group, neuronal apoptosis in the CEPO group was significantly lower at 4, 12, 24, and 48 h (P < 0.05). CEPO significantly inhibited CC3 expression (P < 0.05) during the early-stages after ischemia-reperfusion (0.5, 4, 8, 12 and 24 h), upregulated Bcl-2 expression, and downregulated Bax expression at 4, 8, 12, and 24 h (P < 0.05). CONCLUSIONS: Carbamylated erythropoietin pretreatment inhibited the expression of proapoptotic protein CC3 in brain and regulated the Bcl-2/Bax ratio, resulting in reduced neuronal apoptosis and thus resulting in a protective effect on intrauterine HIE.

Encefalitis autoinmunes: Un nuevo diagnóstico para una antigua enfermedad / Autoimmune encephalitis. New diagnosis for an old condition

Las encefalitis autoinmunes son un nuevo grupo de enfermedades de gran trascendencia clínica y terapéutica debido a la buena respuesta en gran parte de los casos a la terapia inmunomoduladora indicada, con un gran porcentaje de curación, sin secuelas neurológicas importantes (cognitivo, motor, crisis o movimientos involuntarios). En el año 2007 se demostró la presencia de auto anticuerpos neuronales en la patogenia de este grupo de enfermedades, con síntomas psicóticos y de movimientos involuntarios como indicadores de la enfermedad. La presente revisión enfatiza el salto crucial y el cambio de paradigmas suscitados tras el descubrimiento de estas encefalitis asociadas a anticuerpos.

Autoimmune encephalitis is a new group of diseases of great clinical and therapeutic importance due to the good response in most cases to the immunomodulatory therapy indicated, with a large percentage of healing without significant neurological effects (cognitive, motor, seizures or involuntary movements). Since 2007, the presence of neuronal autoantibodies in the pathogenesis of this group of diseases has been demonstrated, with psychotic symptoms and involuntary movements as clinical markers of the disease. The present review emphasizes the crucial leap and change of paradigms arising after the discovery of these encephalitis associated with antibodies.

Esclerose lateral amiotrófica: novas possibilidades terapêuticas em um arcabouço fisiopatológico ainda em construção / Amyotrophic lateral sclerosis: new therapeutic possibilities in a pathophysiological framework still under construction

Introdução: A Esclerose Lateral Amiotrófica (ELA) é definida como uma doença neurológica progressiva e inexorável, com cerca de 80% dos casos de etiologia desconhecida. Novos medicamentos têm emergido no tratamento de doenças neurodegenerativas, inclusive na ELA, redesenhando o modelo fisiopatológico. Dentre eles, destacam-se o uso da: Edaravone, Vitamina K2, Serina, Metilcobalamina, Pirroloquinolina quinona (PQQ), Ubiquinol e Glutationa. Especificamente na ELA, alguns já foram validados em estudos randomizados-controlados. Metodologia: Atualização da literatura (PUBMED, Medline) sobre a utilização desses fármacos em doenças neurológicas degenerativas, com enfoque para a Doença do Neurônio Motor (DNM-ELA), nos idiomas Português, Inglês, Espanhol e Francês, compreendidos entre os anos de (2010-2017). Discussão: A associação desses medicamentos tem mostrado resultados positivos em inúmeras doenças neurológicas. Alguns, como, por exemplo, a Metilcobalamina e o Edaravone,exerceriam mecanismos de ação capazes de interferir no processo de depleção dos neurônios motores da ponta anterior e do feixe piramidal em pacientes com ELA. Conclusão: Seria precipitado concluir que o uso associado desses fármacos poderia modificar ou mesmo restaurar os danos às unidades motoras; entretanto, faz-se necessário destacar seus mecanismos de ação e potencial capacidade de intervir na evolução da doença, principalmente, a partir de estudos em modelos fisiopatológico que culminam na degeneração dos neurônios motores.(AU)

Introduction: Amyotrophic Lateral Sclerosis (ALS) is defined as a progressive and inexorable neurological disease, with about 80% of cases of unknown etiology. New drugs have emerged in the treatment of neurodegenerative diseases, including ALS, redesigning the pathophysiological model. Among them, the use of: Edaravone, Vitamin K2, Serine, Methylcobalamin, Pyrroloquinoline quinone (PQQ), Ubiquinol and Glutathione are noteworthy. Specifically in ALS, some have been validated in randomized controlled trials. Methodology: Update of the literature (PUBMED, Medline) on the use of these drugs in degenerative neurological diseases, with a focus on Motor Neuron Disease (DNM-ELA) in the Portuguese, English, Spanish and French languages, of (2010-2017). Discussion: The association of these drugs has shown positive results in neurological diseases. Some, such as Methylcobalamin and Edaravone, would exert mechanisms of action capable of interfering in the process of depletion of the motor neurons of the anterior horn and pyramidal tracts in patients with ALS. Conclusion: It would be precipitate to conclude that the associated use of these drugs could modify or even restore damage to motor units; however, it is necessary to highlight its mechanisms of action and potential ability to intervene in the evolution of the disease, mainly from studies in pathophysiological models that culminate in the degeneration of motor neurons (AU)

Epidemiological and clinical factors impact on the benefit of riluzole in the survival rates of patients with ALS / Impacto de fatores epidemiológicos e clínicos sobre o benefício do riluzol nas taxas de sobrevida de pacientes com ELA

ABSTRACT Objective To investigate the impact of epidemiological and clinical factors on the benefit of riluzole in patients with amyotrophic lateral sclerosis (ALS). Methods The survival rate of 578 patients with ALS (1999-2011) was analyzed by descriptive statistics and Kaplan-Meier curves. Considering the median of the sample survival time (19 months), patients were divided in two groups: below (B19) and above the median (A19). Kaplan-Meier curves compared the survival rates of patients treated with riluzole and with patients who did not take the medication. Results Riluzole increased the survival rates of patients with lower limb onset who were diagnosed after the first appointment in B19. Patients with bulbar onset and diagnosed on the first, or after the first appointment showed higher survival rates in A19. Males lived longer than females in both groups. Conclusion Epidemiological and clinical factors influenced the benefit of riluzole in the survival rates of patients with ALS.

RESUMO Objetivo Investigar o impacto de fatores epidemiológicos e clínicos sobre o benefício do riluzole em pacientes com esclerose lateral amiotrófica (ELA). Métodos A sobrevida de 578 pacientes com ELA (1999-2011) foi analisada por estatística descritiva e curvas de Kaplan-Meier. Considerando a mediana do tempo de sobrevida (19 meses), a amostra foi subdividida em dois grupos: sobrevida abaixo (B19) e acima de 19 meses (A19). As curvas de Kaplan-Meier compararam a sobrevida de pacientes tratados com riluzole e com pacientes que não receberam tratamento. Resultados O riluzole aumentou a sobrevida de pacientes com início nos membros inferiores e diagnosticados após a primeira consulta no grupo B19. Pacientes com início bulbar e diagnosticados na primeira/ após a primeira consulta apresentaram maior sobrevida em A19. Os homens apresentaram sobrevida maior do que as mulheres. Conclusão Foram encontradas diferenças epidemiológicas e clínicas no benefício do riluzole em pacientes com ELA.

Traumatic spinal cord injury: current concepts and treatment update / Traumatismo raquimedular: conceitos atuais e atualizações terapêuticas

ABSTRACT Spinal cord injury (SCI) affects 1.3 million North Americans, with more than half occurring after trauma. In Brazil, few studies have evaluated the epidemiology of SCI with an estimated incidence of 16 to 26 per million per year. The final extent of the spinal cord damage results from primary and secondary mechanisms that start at the moment of the injury and go on for days, and even weeks, after the event. There is convincing evidence that hypotension contributes to secondary injury after acute SCI. Surgical decompression aims at relieving mechanical pressure on the microvascular circulation, therefore reducing hypoxia and ischemia. The role of methylprednisolone as a therapeutic option is still a matter of debate, however most guidelines do not recommend its regular use. Neuroprotective therapies aiming to reduce further injury have been studied and many others are underway. Neuroregenerative therapies are being extensively investigated, with cell based therapy being very promising.

RESUMO O traumatismo raquimedular (TRM) afeta 1.3 milhão de norte americanos, sendo mais da metade secundário a trauma.No Brasil, pouco estudos avaliaram sistematicamente a epidemiologia do TRM, mas estima-se uma incidência de 16 a 26 por milhão por ano. A extensão final do dano medular é resultante de mecanismos primários e secundários, que começam no momento do evento e prosseguem por dias e até semanas seguintes. Há fortes evidências de que a hipotensão contribua para danos secundários pós TRM. A cirurgia descompressiva visa a aliviar a compressão mecânica sobre a microcirculação, assim reduzindo isquemia e hipóxia. O papel da metilprednisolona no tratamento de pacientes com TRM é controverso, não sendo recomandada pela maior parte das diretrizes atuais. Terapias neuroprotetoras visando a reduzir injúria adicional foram e vêm sendo estudadas. Terapias neurorregenerativas estão sob investigação ampla, sendo a terapia celular uma forte promessa.

Neurocirugía endovascular en el abordaje de pacientes con evento cerebrovascular isquémico / Endovascular neurosurgery in the approach of patients with ischemic cerebrovascular event

El evento cerebrovascular isquémico es una de las principales patologías crónicas de mayor prevalencia a nivel mundial, con tasas altas de mortalidad y discapacidad, con impacto significativo en el ámbito laboral, familiar, social, personal y sanitario. El campo de la neurocirugía endovascular se ha incorporado en las últimas décadas al manejo de enfermedades vasculares, siendo una de las opciones más eficientes para el tratamiento de las mismas por el impacto que tiene sobre la vida del paciente. El presente trabajo de revisión tiene como principal objetivo describir el abordaje de la enfermedad cerebrovascular isquémica aguda, desde su enfoque endovascular, basado en evidencia científica actual y lineamientos vigentes. Se realizó un análisis de los resultados obtenidos en estudios clínicos y de los protocolos más recientes publicados en artículos de revisión de bibliotecas virtuales y revistas científicas con rigurosas normas de publicación. Conforme a la revisión realizada, el tratamiento de la enfermedad cerebrovascular isquémica aguda puede abordarse de dos maneras dependiendo del tiempo transcurrido desde el inicio de los síntomas. Si únicamente han transcurrido 4.5 horas desde el inicio de los síntomas y el paciente cumple con criterios bien establecidos, el tratamiento de elección será trombólisis IV (tratamiento estándar). Si han transcurrido más de 4.5 horas (máximo 12 hrs.) o paciente presenta alguna contraindicación para recibir el tratamiento estándar, se deberá manejar con trombólisi intraarterial, trombólisis combinada, trombectomía mecánica o angioplastía con stent (cirugía de precisión); todos ellos definidos como tratamiento endovascular, según sea el caso. El tratamiento endovascular ha permitido ampliar el periodo de atención del evento cerebrovascular isquémico, demostrando su efectividad y reduciendo la discapacidad y mortalidad asociadas...(AU)

The ischemic cerebrovascular event is one of the most important chronic diseases because of its highest prevalence worldwide. It has high rates of mortality and disability, with a significant impact in the labor, family, social, personal and health areas. The field of endovascular neurosurgery has been incorporated in the last decades to the management of vascular diseases; being one of the most efficient options for their treatment because of its effect in patient´s life expectancy. The main objective of this review was to describe the endovascular approach to acute ischemic cerebrovascular disease based on current scientific evidence and guidelines. An analysis of clinical studies and recent protocols was done. According to this review, treatment of acute ischemic cerebrovascular disease can be approached in two ways depending on the time elapsed since the onset of symptoms. If only 4.5 hours have elapsed since the onset of symptoms and the patient meets all inclusion criteria, the treatment of choice will be IV thrombolysis (standard treatment). If more than 4.5 hours have elapsed (maximum 12 hours) or patient has any contraindication to receive standard treatment, it should be treated with intra-arterial thrombolysis, combined thrombolysis, mechanical thrombectomy or angioplasty with stenting; all defined as endovascular treatment. The endovascular treatment has allowed to extend the period of attention of the ischemic cerebrovascular event, demonstrating its effectiveness and reducing the associated disability and mortality...(AU)

Histopathologic comparison of dexmedetomidine's and thiopental's cerebral protective effects on focal cerebral ischemia in rats / Comparação histopatológica dos efeitos protetores cerebrais de dexmedetomidina e tiopental sobre isquemia cerebral focal em ratos

Abstract This study was designed to investigate whether dexmedetomidine and thiopental have cerebral protective effects after focal cerebral ischemia in rats. Thirty male Sprague Dawley rats were randomly assigned to three groups: control group (Group C, n = 10), dexmedetomidine group (Group D, n = 10), thiopental group (Group T, n = 10). After all rats were anesthetized, they were intubated, then mechanically ventilated. A catheter was inserted into the right femoral artery for continuous mean arterial pressure, physiological parameters and blood sampling at baseline, 5 min after occlusion and 20 min after reperfusion. A catheter was inserted into the left femoral vein for intravenous (IV) medication administration. Right common carotid artery of each rat was isolated and clamped for 45 min. At the end of the duration common carotid artery were unclamped and the brain reperfusion was achieved for 90 min. Dexmedetomidine was administered for Group D IV infusion, and Group T received thiopental IV. According to histopathologic scores cerebral ischemia was documented in all rats in Group C, but no ischemia was found in three rats in Group T and in four rats in Group D. Grade 3 cerebral ischemia was documented in three rats in Group C, and in only one rat in both groups T and D. For histopathologic grades the difference between Group T and Group D was not significant (p > 0.05). But the differences between Group C and Group T (p < 0.05) and Group C and Group D (p < 0.01) were statically significant. In conclusion, we demonstrated that dexmedetomidine and thiopental have experimental histopathologic cerebral protective effects on experimental focal cerebral ischemia in rats.

Resumo Este estudo foi desenhado para investigar se dexmedetomidina e tiopental têm efeitos protetores cerebrais após isquemia cerebral focal em ratos. Trinta ratos da linhagem Sprague Dawley foram randomicamente alocados em três grupos: controle (Grupo C, n = 10), dexmedetomidina (Grupo D, n = 10) e tiopental (Grupo T, n = 10). Após a anestesia, foram intubados e ventilados mecanicamente. Um cateter foi inserido na artéria femoral direita para monitoração contínua da pressão arterial média (PAM) e dos parâmetros fisiológicos e para coleta de amostras de sangue na fase basal, 5 minutos após a oclusão e 20 minutos após a reperfusão. Um cateter foi inserido na veia femoral esquerda para administração intravenosa (IV) de medicamentos. A artéria carótida comum direita de cada rato foi isolada e pinçada durante 45 minutos. No fim dos 45 minutos, o pinçamento foi removido e a reperfusão do cérebro foi obtida por 90 minutos. Dexmedetomidina foi administrada por infusão IV no Grupo D e tiopental no Grupo T. De acordo com as pontuações histopatológicas, isquemia cerebral foi observada em todos os ratos do Grupo C, mas não foi encontrada em três ratos do Grupo T e em quatro ratos do Grupo D. O grau 3 de isquemia cerebral foi encontrada em três ratos do grupo C e em apenas um rato de ambos os grupos T e D. Para os graus histopatológicos, a diferença entre o Grupo T e o Grupo D não foi significativa (p > 0,05). Porém, as diferenças entre o Grupo C e o Grupo T (p < 0,05) e entre o Grupo C e o Grupo D (p < 0,01) foram estatisticamente significativas. Em conclusão, demonstramos que dexmedetomidina e tiopental têm efeitos histopatológicos protetores cerebrais sobre isquemia cerebral focal experimental em ratos.

LXW7 ameliorates focal cerebral ischemia injury and attenuates inflammatory responses in activated microglia in rats

Inflammation plays a pivotal role in ischemic stroke, when activated microglia release excessive pro-inflammatory mediators. The inhibition of integrin αvβ3 improves outcomes in rat focal cerebral ischemia models. However, the mechanisms by which microglia are neuroprotective remain unclear. This study evaluated whether post-ischemic treatment with another integrin αvβ3 inhibitor, the cyclic arginine-glycine-aspartic acid (RGD) peptide-cGRGDdvc (LXW7), alleviates cerebral ischemic injury. The anti-inflammatory effect of LXW7 in activated microglia within rat focal cerebral ischemia models was examined. A total of 108 Sprague-Dawley rats (250–280 g) were subjected to middle cerebral artery occlusion (MCAO). After 2 h, the rats were given an intravenous injection of LXW7 (100 μg/kg) or phosphate-buffered saline (PBS). Neurological scores, infarct volumes, brain water content (BWC) and histology alterations were determined. The expressions of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], and Iba1-positive activated microglia, within peri-ischemic brain tissue, were assessed with ELISA, western blot and immunofluorescence staining. Infarct volumes and BWC were significantly lower in LXW7-treated rats compared to those in the MCAO + PBS (control) group. The LXW7 treatment lowered the expression of pro-inflammatory cytokines. There was a reduction of Iba1-positive activated microglia, and the TNF-α and IL-1β expressions were attenuated. However, there was no difference in the Zea Longa scores between the ischemia and LXW7 groups. The results suggest that LXW7 protected against focal cerebral ischemia and attenuated inflammation in activated microglia. LXW7 may be neuroprotective during acute MCAO-induced brain damage and microglia-related neurodegenerative diseases.

Aquisição de medicamentos para a Doença de Alzheimer no Brasil: uma análise no sistema federal de compras, 2008 a 2013 / The acquisition of medication to treat Alzheimer´s disease in Brazil: an analysis of federal purchases, 2008-2013

Resumo O processo de transição demográfica brasileiro tem levado a substancial envelhecimento populacional e a aumento na prevalência de síndromes demenciais, entre as quais se destaca a Doença de Alzheimer (DA). Desde 2002, o tratamento farmacológico da doença possui Protocolo Clínico e Diretrizes Terapêuticas (PCDT) específico e os medicamentos recomendados são de financiamento pelo Ministério da Saúde. O estudo investigou a aquisição dos medicamentos utilizados no tratamento da DA a partir do Sistema Integrado de Administração de Serviços Gerais, traçando um perfil evolutivo das quantidades adquiridas, gastos e preços praticados no período de 2008 a 2013. Foram analisados os dados relativos a todas as apresentações adquiridas, inclusive as ausentes do PCDT. Os preços unitários foram deflacionados para dezembro/2013, pelo IPCA. Foram compradas mais de 47 milhões de unidades e gastos R$ 90,1 milhões com medicamentos para DA. Destaca-se nos gastos a participação da rivastigmina em suas diversas apresentações. Medicamentos não indicados pelo PCDT representaram 3% dos gastos, com percentuais de compra associados ao atendimento de ações judiciais pouco expressivos. No período, ocorreu redução dos preços médios ponderados corrigidos de todos os medicamentos, mesmo dos não presentes no PCDT.

Abstract The demographic transition in Brazil has led to substantial aging of the population and an increased prevalence of age-related diseases such as dementia and Alzheimer’s Disease (AD). The Brazilian Ministry of Health finances AD medication and, since 2002, a Clinical Protocol and Therapeutic Guidelines (PCDT) for this condition have been made available. This study investigated the acquisition of medication for AD in the Integrated System of Administration of General Services (SIASG) database. A profile of purchases, expenditures and prices from 2008 to 2013 was prepared. All medication and forms of treatment of AD were investigated, including those not contained in the PCDT protocol. Unit prices were deflated to December 2013 by the IPCA (Brazilian Pricing Index). More than 47 million units of medication for AD were acquired and expenditures attained 90.1 million Brazilian reals. The purchase of the various administration routes of rivastigmine were in the forefront. Medication not listed in the protocol represented 3% of expenditures and purchases resulting from health litigation were negligible. Over the period, a reduction of corrected weighted average prices of PCDT and non-PCDT medication was observed.

Neuroprotección por ácido valproico y cambios en la expresión de Bcl-2 y caspasa-3 activada en ratas sometidas a isquemia/reperfusión / Neuroprotective action of valproic acid accompanied of the modification on the expression of Bcl-2 and activated caspase-3 in the brain of rats submitted to ischemia/reperfusion

El ácido valproico, que además de ser un conocido antiepiléptico, una serie de trabajos en los últimos años lo proponen como un agente neuroprotector. En éste trabajo se investigó primeramente, si el ácido valproico protege a las neuronas del daño producido por el estrés oxidativo inducido por la isquemia-reperfusión en el cerebro de ratas sanas sometidas a la oclusión transitoria de la arteria cerebral media derecha; en segundo lugar, se indagó si este fármaco induce cambios en la expresión de Bcl-2 y caspasa 3-activada como un posible mecanismo de acción sobre la muerte celular del tipo apoptótico. La evaluación neurológica de los animales que fueron sometidos a isquemia/reperfusión y recibieron ácido valproico fue mejor que los que no lo recibieron. Por otro lado, los niveles de malondialdehído en el hemisferio cerebral derecho en las ratas tratadas con ácido valproico fueron inferiores a los del mismo hemisferio del grupo control, mientras la cantidad de proteínas carboniladas se redujeron un 67% en comparación al grupo control. Además, se encontró por western blot, que en homogeneizados de tejido cerebral de los animales sometidos a isquemia/reperfusión y que recibieron ácido valproico, hubo un aumento significativo de la densidad de las bandas correspondientes a Bcl-2 y una disminución de caspasa 3-activada en comparación a los que no fueron tratados con este fármaco. Se concluye que el tratamiento con ácido valproico previno el déficit neurológico en ratas sanas sometidas a isquemia-reperfusión, bloqueando el efecto de los radicales libres sobre lípidos y proteínas de la corteza cerebral afectada y se sugiere que posiblemente este fármaco interviene en la muerte por apoptosis inducida durante este tipo de lesión, pudiendo ser una alternativa terapéutica en el tratamiento de la isquemia cerebral.

Valproic acid, apart from being known as an anti-epileptic drug, has been proposed in the past few years, as a neuroprotective agent. The purpose of this study was to investigate firstly, if valproic acid protects the neurons from the damage produced by oxidative stress induced by ischemia-reperfusion in the brain of healthy rats, under the transitory occlusion of the right middle cerebral artery. Secondly it was studied if this antiepileptic drug induces changes on the expression of Bcl-2 and activated caspase-3 as a possible mechanism of action on apoptosis. The neurological evaluation of the animals that were subject to ischemia-reperfusion and received valproic acid was better than the ones who didn’t receive it. On another subject, the levels of malondialdehyde on the right cerebral hemisphere in the rats treated with valproic acid were below the levels of the control group in the same hemisphere, whereas the amount of carbonylated proteins was reduced by 67% compared to the control group. Besides, it was found by western blot, that in homogenized brain tissue of the animals under ischemia-reperfusion which received valproic acid, there was a rise on the density of the bands corresponding to Bcl-2, and a reduction of activated 3-capase in comparison to the ones who were not treated with the antiepileptic drug. It’s concluded that the treatment with valproic acid prevented the neurological deficit in healthy rats under Ischemia-reperfusion, blocking the effect of free radicals on lipids and proteins of the affected brain cortex, and it is suggested that the same drug intervenes on apoptosis induced during this type of damage, being able to be a therapeutic alternative in the treatment of cerebral ischemia.

Effects of estrogen on functional and neurological recovery after spinal cord injury: An experimental study with rats

OBJECTIVES:To evaluate the functional and histological effects of estrogen as a neuroprotective agent after a standard experimentally induced spinal cord lesion.METHODS:In this experimental study, 20 male Wistar rats were divided into two groups: one group with rats undergoing spinal cord injury (SCI) at T10 and receiving estrogen therapy with 17-beta estradiol (4mg/kg) immediately following the injury and after the placement of skin sutures and a control group with rats only subjected to SCI. A moderate standard experimentally induced SCI was produced using a computerized device that dropped a weight on the rat's spine from a height of 12.5 mm. Functional recovery was verified with the Basso, Beattie and Bresnahan scale on the 2nd, 7th, 14th, 21st, 28th, 35th and 42nd days after injury and by quantifying the motor-evoked potential on the 42nd day after injury. Histopathological evaluation of the SCI area was performed after euthanasia on the 42nd day.RESULTS:The experimental group showed a significantly greater functional improvement from the 28th to the 42nd day of observation compared to the control group. The experimental group showed statistically significant improvements in the motor-evoked potential compared with the control group. The results of pathological histomorphometry evaluations showed a better neurological recovery in the experimental group, with respect to the proportion and diameter of the quantified nerve fibers.CONCLUSIONS:Estrogen administration provided benefits in neurological and functional motor recovery in rats with SCI beginning at the 28th day after injury.